Daily Endocrinology Research Analysis

IMPORTANCE: Historically considered a skeletal dysplasia characterized by disproportionate short stature, achondroplasia is a condition with multisystemic effects due to the widespread expression of the fibroblast growth factor receptor 3 variant throughout the body, impacting muscle, neurological function, cardiorespiratory health, and health-related quality of life. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of once-weekly navepegritide, an investigational prodrug of C-type natriuretic peptide, while assessing benefits beyond growth that may have important implications for complications and health-related quality of life in children with achondroplasia. DESIGN, SETTING, AND PARTICIPANTS: Enrollment for this pivotal phase 2b, randomized, double-blind, placebo-controlled trial (APPROACH) was conducted between March and August 2023 at 10 hospitals in Australia, Canada, Denmark, Ireland, New Zealand, Spain, and the US with randomized, blind treatment through 52 weeks and an open-label extension (ongoing). Eligible participants aged 2 to 11 years had achondroplasia confirmed by genetic testing, were naive to treatment with growth-promoting agents, and had their height recorded at least 6 months prior to randomization. Enrolled participants were stratified by age and sex. Those with radiographic evidence of closed growth plates, planned bone surgery, severe untreated sleep apnea, or medical conditions known to affect growth were excluded (n = 2 of 86); of 84 participants enrolled, all were analyzed for safety and efficacy outcomes, including 2 who discontinued treatment. INTERVENTIONS: Navepegritide (100 μg/kg/wk) or placebo administered by once-weekly subcutaneous injection. MAIN OUTCOMES AND MEASURES: The primary end point was annualized growth velocity at week 52. Other clinically important secondary measures included radiographically assessed skeletal outcomes and health-related quality of life, evaluated using Achondroplasia Child Experience Measures. Safety assessments included adverse events, clinical laboratory assessments, bone age, and immunogenicity. RESULTS: Eighty-four participants were enrolled and assigned randomly in a 2:1 ratio to receive navepegritide (n = 57; mean [SD] age, 5.6 [2.6] years; 31 [54%] male) or placebo (n = 27; mean [SD] age, 6.0 [2.7] years; 14 [52%] male). All randomized participants were included in efficacy and safety analyses, although 2 patients in the navepegritide group discontinued treatment (one at week 26 and the other at week 34). The trial met its primary end point, demonstrating superiority of navepegritide in annualized growth velocity at week 52 vs placebo (least-squares mean treatment difference of 1.49 cm/y; 95% CI, 1.05 to 1.93; P < .001). Treatment resulted in improvements (least-squares mean treatment difference [95% CI]) in tibial-femoral angle (-1.81° [-3.16 to -0.47]), mechanical axis deviation (-2.78 mm [-4.71 to -0.86]), and fibula to tibia length ratio (-0.016 [-0.024 to -0.008]), and Achondroplasia Child Experience Measures-Physical Functioning (-11.1 [-21.5 to -0.80] in children younger than 5 years). No serious adverse events were treatment-related, and no deaths occurred. Injection site reaction rates were low, and no symptomatic hypotension or fractures were observed. CONCLUSIONS: In this randomized clinical trial, navepegritide treatment resulted in statistically significantly higher annualized growth velocity in children with achondroplasia, with a similar safety and tolerability profile vs placebo. Moreover, navepegritide demonstrated additional potential health benefits beyond growth. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05598320.

BACKGROUND: Current guidelines for polycystic ovary syndrome (PCOS) recommend combined oral hormonal contraceptives as first-line pharmacological treatment to reduce androgen excess and to treat clinical hyperandrogenic skin manifestations, such as hirsutism. However, these are used off-label. We aimed to demonstrate the efficacy of a prolonged-release oral formulation in a 24/4-day regimen for up to nine 28-day consecutive cycles compared with placebo for the clinical management of hirsutism in women with PCOS. METHODS: This was a multinational, multicentre, double-blind, placebo-controlled trial done across 46 sites in Czech Republic, Hungary, Lithuania, Poland, Serbia, Slovakia, Spain and Ukraine. Eligible participants were 2-year-post-menarche women (14-40 years old) with a body mass index (BMI) of 18 to <35 kg/m FINDINGS: Between Nov 2, 2021, and Dec 5, 2023, of 500 patients screened, 305 participants were enrolled and randomised to study groups and 202 participants completed the trial to the end of Cycle 9. The safety set comprised 291 participants (DNG + EE, n = 234; placebo, n = 57) and 256 participants were included in the full analysis set (FAS; DNG + EE, n = 209; placebo, n = 47). 76 (DNG + EE) and 27 (placebo) participants discontinued the trial early, including 18 and four who discontinued due to adverse events; 168 and 34 participants, respectively, completed the trial. Least squares (LS) mean changes from baseline to end of Cycle 9/EDV in adapted mFG score were -3.8 and -1.5 for the DNG + EE and placebo groups, respectively (difference -2.24 ± 0.49 (98.75% CI: -∞, -1.14; p < 0.0001; MMRM, FAS). In the ≤30 and > 30 kg/m INTERPRETATION: Our findings show that oral prolonged-release DNG 2 mg plus EE 0.2 mg in a 24/4-day regimen for up to 9 cycles is an effective treatment for hirsutism in women with PCOS, with an acceptable safety profile. Further research is required to assess DNG + EE in treating hirsutism among different cultural and ethnic populations as well its impact on mood disorders (depression and anxiety) in women with hirsutism-associated PCOS. FUNDING: Chemo Research S.L.

UNLABELLED: Preclinical studies show that dietary or central administration of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) can reduce food intake, enhance energy expenditure, and attenuate hypothalamic inflammation (HI), whereas saturated fatty acids (SFAs) promote weight gain, HI, and neuronal injury. However, whether hypothalamic exposure to different fatty acids similarly influences HI and body weight in humans remains unclear. In this longitudinal study, we compared cerebrospinal fluid (CSF) free fatty acid (FFA) profiles between 19 normal-weight control participants and 44 individuals with obesity, both at baseline and 1 year after bariatric surgery (BS). We also examined associations between CSF FFA composition, MRI-based markers of HI (i.e., increased hypothalamic mean diffusivity [MD] and volume), and postoperative weight loss. At baseline, individuals with obesity had similar CSF concentrations of total FFA, SFA, and MUFA compared with control participants but significantly lower PUFA levels, mainly due to reduced docosahexaenoic acid (DHA) levels. BS did not substantially alter CSF FFA profiles. Lower baseline CSF DHA levels were associated with higher hypothalamic MD and independently predicted less weight loss at 1 year. Postoperative increases in CSF DHA levels correlated with reductions in hypothalamic MD. These findings suggest brain DHA level may influence hypothalamic microstructure and contribute to body weight regulation in human obesity. ARTICLE HIGHLIGHTS: Whether hypothalamic exposure to free fatty acid (FFA) species contributes to obesity and hypothalamic inflammation (HI) in humans is not yet defined. We compared cerebrospinal fluid FFA profiles between normal-weight control participants and individuals with obesity, before and after bariatric surgery (BS), and examined their associations with postoperative weight trajectories and neuroimaging biomarkers of HI. Individuals with obesity had reduced cerebrospinal fluid levels of docosahexaenoic acid (DHA) before and after BS. Lower cerebrospinal fluid DHA levels correlated with biomarkers of HI and were independently associated with less weight loss after BS. The findings highlight the potential of DHA in modulating hypothalamic function.